Hydrogels and methods for their production

ABSTRACT

The present invention relates to new hydrogels with improved mechanical properties and methods of their preparation. The hydrogels are formed from hydrophilic polymers having function hydroxyl groups and have low elasticity modulus typically less than about 10 kPa, a tensile strength above 1 Mpa, an elongation above 50% which makes suitable as medical implants, in particular intraocular lenses. The hydrogels are prepared by a crosslinking method with a comparatively low concentration of hydrophilic polymer of a sufficiently high molecular weight dissolved in a good solvent.

BACKGROUND OF THE INVENTION

Hydrogels have found numerous applications in medical technology, forexamples in implants or as drug delivery devices. A drawback withconventional hydrogels, such as polyHEMA (hydroxyethylmethacrylate), istheir brittleness due to their low tensile strength in swollen state,which is about 0.5 MPa. This characteristic is especially problematicduring surgical intervention when an implant made from a hydrogelmaterial shall be inserted into the body often with complexmanipulations, as is the case when a hydrogel intraocular lens (IOL)shall be positioned in the capsular bag of the eye through a smallincision. Another drawback for the application of conventional hydrogelsas medical implants is their high elasticity modulus. In the techniqueof replacing the natural lens of the eye with a hydrogel IOL, their highmodulus prevents the implant from being accommodatable under theinfluence of the compressing and relaxing forces exerted by the ciliarymuscles. It is also prerequisite in an ophthalmic application that therefractive index should be sufficiently high. This implies that theswollen network should contain a sufficient amount of water. Obviouslythere is a demand for new hydrogel materials that can overcome thementioned disadvantages.

It is the object of the present invnetion to provide for hydrogels,which at a high water content have suitably high tensile strength andsufficiently low elasticity modulus to improve their usefulness asmedical implants.

It is also an object of the present invnetion to provide for a method ofpreparing such hydrogels.

DESCRIPTION OF INVENTION

The present invention refers to new hydrogels with improved mechanicalcharacteristics that makes them highly applicable as implants in thehuman body. In this context hydrogel is defined as a polymer compositionthat is swellable in water to an equilibrium value. Such a polymercomposition comprises a network of a hydrophilic polymer. A network of ahydrophilic polymer typically means that crosslinks are formed betweenpolymer chains by covalent bonds or by physical bonds, e.g. hydrogenbonds. A hydrophilic polymer according to the present invention isdefined as a polymer capable of swelling in water, however, not beingsoluble in water. The hydrophilic polymer is generally described to havea carbon to carbon backbone —(C—C—C—C)_(n)— to which functional groupshaving an active hydrogen are attached so the polymer is provided withhydrophilic characteristics and points for crosslinking. According to ahighly preferred aspect of the present invention, the functional groupsare hydroxyl groups. The hydroxyl groups can either be attached directlyto the carbon to carbon backbone or be a functional group in a chainattached to said backbone thus providing a polyhydroxy polymer.Preferably, this type of hydrophilic polymers has no other functionalgroups than hydroxyl. Especially suitable such hydrophilic polymers arefound among the following: —(CH₂—CHOH)_(n)— (polyvinyl alcohol);—(CH₂—CH₂)_(n)(CH₂—CHOH)_(m)— (copolymer of ethylene and vinyl alcohol);—(CH₂—CH₂—CHOH)_(n)— and —(CH₂—CH(CH₂OH))_(n)— (polyallyl alcohol).Polyvinyl alcohol is normally a water-soluble polymer and within thiscontext it is therefore subjected to chemical modification to obtainhydrophilic properties according the earlier given definition. Thesementioned polymers and their methods of production are well known to theskilled practitioner and will not be discussed here in greater detail.It would be conceivable for the person skilled in polymer chemistry toselect suitable qualities of these polymers to be applicable within thecontext of the present invention. It is also to be understood thatfunctional analogues and derivatives of the mentioned suitable polymersshall be regarded to be a part of the present invention when it isdescribed in more general terms.

The present invnetion in its most general form refers to hydrogelscomprising a network of hydrophilic polymers having hydroxyl groupcarrying carbon-carbon backbones having specifically advantageousmechanical characteristics making suitable as implants, especiallyocular implants. The hydrogels typically have an elasticity modulus lessthan about 10 kPa, preferably less than about 5 kPa which issufficiently low to render them useful as accommodatable intraocularlenses. Furthermore, the hydrogels have an elongation of at least 50% atequilibrium water content and a tensile strength of at least about 1MPa, suitably above about 5 MPa, which provides them a sufficientstrength so thin foldable implants (e.g. intraocular lenses) can beproduced. The hydrogels can be made with a sufficient optical clarity,so as to obtain an optical transmission of at least about 40% and asuitably high a refractive index of at least about 1.40.

It is an important feature of the present invention that the hydrophilicpolymers from which the hydrogels are formed have sufficiently highindividual molecular weight. It has been found that an insufficientmolecular weight of the hydrophilic polymers forming the hydrogels canimpair both the strength and optical quality and create flaws in theproducts. Therefore it is suitable that the molecular weight is at least200 000. Preferably, the molecular weight is at least 300 000, beforethey are assembled in a network by, for example a crosslinking reaction.The relationship between molecular weight and crosslinking density willbe discussed below in more detail. The inventive hydrogels have ageneral polymer content between about 30 to 80% (wt), preferably betweenabout 40 to 70% (wt) and more preferably between about 40 to 60%.

According to an embodiment of the present invention, the hydrophilicityof the polymers is reduced by chemically modifying the hydrophilicpolymers. Thereby, the equilibrium water content of the hydrogels isreduced. This step can be necessary for certain water-soluble polymersbefore they are applicable in the inventive context and will comply withthe definition of “hydrophilic” as given above. An example of such apolymer is poly(vinylalcohol). A suitable agent for such chemicalmodification is a monoisocyanate capable of reacting with the hydroxylgroups of the hydrophilic polymers. Suitable such monoisocyanates arefound among lower alkyl, aryl or arylalkyl isocyanates. One example of asuitable monoisocyanate is n-butylisocyanate, or if a less hydrophobicisocyanate is preferred ethylisocyanate. Preferably, this type ofmodification is random along the polymer backbone. Suitable hydrophilicpolymers for the hydrogels are selected among polymers having a carbonto carbon backbone only substituted with hydrogen, hydroxyl andhydroxyalkyl, wherein alkyl is a lower alkyl having six or less carbonatoms. A preferred hydroxyalkyl is hydroxymethyl. Especially suitableare at least one of the polymers —(CH₂—CHOH)_(n)— (polyvinyl alcohol);—(CH₂—CH₂)_(n)(CH₂—CHOH)_(m)— (copolymer of ethylene and vinyl alcohol);—(CH₂—CH₂—CHOH)_(n)— (poly(1-hydroxy-1,3-propanediyl) and—(CH₂—CH(CH₂OH))_(n)— (polyallylalcohol). Consequently it is preferredthat the hydrogels includes one of these polymers.

According to a preferred embodiment the network of the hydrogels isformed by crosslinks in the form of covalent bonds between thehydrophilic polymers. In one first preferred aspect of this embodiment,the crosslinks are formed by reacting hydroxyl groups of the hydrophilicpolymers with a crosslinkable amount of a diisocyanate having a generalformula ONC—R—CNO, thereby providing urethane bonds—O—C(O)—NH—R—NH—C(O)—O— between the polymer chains, wherein R is aspacing group. R can be an optionally substituted lower alkyl grouphaving between one and ten carbon atoms, such as —(CH₂)₄—. Suitablediisocyanates for the crosslinking are 1,4-butanediisocyante,1,6-hexanediisocyanate and lysine-diisocyanate and the diisocyanatehaving the formula OCN—(CH₂)₄—NH—C(O)O—(CH₂)₄—O(O)C—NH—(CH₂)₄—CNO with apreference for 1,4-butanediisocyanate. The skilled person in this fieldwill be able to find alternative diisocyanates to these mentioned andyet operate within the context of the invention. In a second aspect ofthis embodiment the crosslinks can be formed by epoxy-compound, such asepichlorohydrine or isophorone. An epoxy-compound useful in this contextpreferably has two epoxy groups spaced apart by a suitable chain.

It is a characteristic feature of this embodiment that the crosslinkingdensity is kept low, preferably it less than about 10%, preferably lessthan 5%. In some applications the crosslinking density can be reduced to3% and even to 1%, given that the specifically mentioned importantmechanical characteristics of the resulting hydrogels in such a case canbe retained or improved by correspondingly increasing the molecularweight of the hydrophilic polymers. It is found within the context ofthe present invention that suitable hydrogels can be obtained with verylow crosslinking density such as in the range of about 0.5 to 3% if themolecular weight of hydrophilic polymers is correspondingly increased. Aparticularly suitable hydrogel comprises crosslinkedpoly(1-hydroxy-1,3-propanediyl)which optionally has been modified beforecrosslinking with a low degree (less than 10%) of monoisocyanate tomodulate its hydrophilicity (i.e. equilibrium water content). Suitably,the poly(1-hydroxy-1,3-propanediyl) is crosslinked with a lower alkyldiisocyante, most suitably 1,4-butanediisocyanate. A specific example ofa hydrogel according to the present invention is based onpoly(1-hydroxy-1,3-propanediyl having about 5% of its hydroxyl groupsmodified with n-butyl-isocyanate and crosslinked with1,4-butanediisocyante to densities varying between 1 and 5%. Such ahydrogel is found to have excellent mechanical and optical properties,which are particularly desirable in intraocular lenses capable ofundergo accommodation when subjected to the forces of ciliary muscles ofthe eye.

In another embodiment of the invention the hydrogels comprisepolyallylalcohol as a hydrophilic polymer in the network withoutcrosslinks (i.e. covalent bonds) between the polymer chains. In thisalternative, the characteristics of the hydrogel can optionally becontrolled by the amount of chemical modification (e.g. amountintroduced monoisocyanate groups) of the hydrophilic polymer chains andthe molecular weight of the polymer.

The present invention is also directed to a method of preparinghydrogels with low elasticity moduli. The inventive method is based onthe findings that a hydrogel with surprisingly low modulus is obtainableif a low concentration of the polymer and sufficiently high molecularweight is selected for the preparation process. Hydrogels withelasticity moduli as low as below about 10 kPa, or even below about 5kPa are attainable with the inventive method, while yet obtainingexcellent other mechanical and optical characteristics of the hydrogelincluding a sufficiently high tear strength. In a general form, themethod comprises the steps of selecting hydrophilic polymer ofsufficiently high molecular weight; dissolving said polymer in a goodsolvent to a concentration not exceeding about 5% (wt); adding acrosslinking agent; mixing and reacting polymer with crosslinker;evaporating said solvent and finally optionally adding water. A goodsolvent is defined herein to be a solvent which is capable of generatinga minimum amount of trapped entanglements and entangled polymer chainends, so the polymer chains are stretched out rather than collapsed.Trapped entanglements, loops and problems with dangling polymer chainends can be avoided with a good solvent. Thereby flaws and other networkdefects in hydrogel will be reduced to a minimum, so a more homogenousnetwork is formed. It is also an important aspect of the inventivemethod to select a sufficiently high molecular weight of the hydrophilicpolymers. It is suitable that the hydrophilic polymer has a molecularweight of at least about 200 000, preferably at least about 300 000. Asufficiently high molecular weight will contribute to improve thehomogeneity of the network by reducing the amount of dangling polymerchain ends. The hydrophilic polymers suitable to employ in the inventivemethod are found among polymers having a carbon to carbon backbone towhich functional hydroxyl groups for crosslinking are attached. In ageneral meaning the method is applicable also for other types ofhydrophilic polymers having other types of functional groups forcrosslinking given that the above mentioned general requirements aremet. Suitable hydrophilic polymers for the hydrogels are selected amongpolymers having a carbon to carbon backbone only substituted withhydrogen, hydroxyl and hydroxyalkyl, wherein alkyl is a lower alkylhaving six or less carbon atoms. A preferred hydroxyalkyl ishydroxymethyl. Especially suitable is at least one of the polymers—(CH₂—CHOH)_(n)— (polyvinyl alcohol); —(CH₂—CH₂)_(n)(CH₂—CHOH)_(m)—(copolymer of ethylene and vinyl alcohol); —(CH₂—CH₂—CHOH)_(n)—(poly(1-hydroxy-1,3-propanediyl)) and —(CH₂—CH(CH₂OH))_(n)—(polyallylalcohol). According one embodiment of the inventive method,the hydrophilic properties of the polymers is reduced in advance of thecrosslinking by chemical modification. The modification of thehydrophilic properties is preferably performed by reacting a fraction ofthe hydroxyl groups of the polymers with monoisocyanate. The degree ofmodification is suitably less than 15% and preferably less than 10%. Inone example poly(1-hydroxy-1,3-propanediyl is modified to a degree ofabout 5%. Suitable monoisocyanates for this step of the method have beendiscussed earlier in the specification. Suitable crosslinkers have alsobeen discussed earlier. One example is diisocyanates having a formulaOCN—R—CNO defined as above. An example of such a suitable diisocyanateis 1,4-butane-diisocyanate.

Furthermore, the inventive method involves steps of degassing thesolution of polymer in good solvent before conducting the crosslinkingreaction and performing the crosslinking at a constant volume.

The following detailed part of the description describes suitableexperimental conditions to obtain the inventive hydrogels and themethods for their preparations. Also described therein are illustrativeexamples of the present invention, which shall not be regarded aslimiting for the invention as claimed in the appended set of claims.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 shows equilibrium water content as a function of crosslinkdensity for a poly(1-hydroxy-1,3-propanediyl based network (BDI.BDO.BDIcrosslinker).

FIG. 2 shows tensile strength as a function of crosslink density forwater-swollen, BDI based poly(1-hydroxy-1,3-propanediyl) network.

FIG. 3 shows tensile strength as a function of crosslink density forboth a dry and a swollen BDI.BDO.BDI basedpoly(1-hydroxy-1,3-propanediyl) 1 network.

FIG. 4 shows the equilibrium water content as a function of temperaturefor poly(1-hydroxy-1,3-propanediyl) network 1.

FIG. 5 shows equilibrium water content as a function of temperature forpolyalcohol network 2.

FIG. 6 shows equilibrium water content as a function ofn-butylisocyanate percentage.

FIG. 7 shows DSC traces of polyalcohol system 2: 0.5% crosslinker and 5%n-butylisocyanate.

FIG. 8 shows the dependence of the Tg on the percentage of side groups.

FIG. 9 shows a stress-strain curve of poly(1-hydroxy-1,3-propanediylnetwork with 5% n-butylisocyanate and 0.5% BDI.BDO.BDI crosslinker; dryand water-swollen.

FIG. 10 shows stress-strain curves of drypoly(1-hydroxy-1,3-propanediyl) networks with 5, 10 and 25% ofn-butylisocyanate groups.

FIG. 11 shows stress-strain curves of water swollenpoly(1-hydroxy-1,3-propanediyl) networks with 5, 10 and 25% ofn-butylisocyanate groups.

FIG. 12 shows the determination of the permanent deformation ofpolyalcohol network 2;

first cycle; ------- third cycle.

FIG. 13 shows a DSC thermogram of dry polyallylalcohol.

EXPERIMENTAL

Materials and Methods

All reactions were performed under an inert atmosphere of nitrogen gasin flame-dried glassware.

Polyvinylalcohol (99+% hydrolyzed, Mn˜130.000) was synthesized from highmolecular weight polyvinylacetate (Aldrich Chemical Company Inc.)according to Sakurada, I.; Fujiwara, N. Kobunshi Kagaku 1945, 2, 143.Polyallylalcohol was obtained by reduction of high molecular weightpolymethylacrylate with lithium aluminum hydride following Schulz, R.C.; Elzer, P. Makromol. Chem. 1961, 42, 205. Polyvinylalcohol-co-ethylene (Aldrich Chemical Company Inc., ethylene content 27mole %) and n-butylisocyanate (Aldrich Chemical Company Inc.) were usedas received.

Poly(1-hydroxy-1,3-propanediyl) (PHP or “polyalcohol”) was synthesizedfrom polyketone (Carilon, LVN/[η]=6.7, Mv˜450.000, Akzo-Nobel DobbsFerry) according to the procedure of Lommerts, B. J.; Ph.D. Thesis,University of Groningen, The Netherland, 1994. However, three additionalpurification steps were added. The crude PHP was dissolved in NMP (1%w/w) at 60° C. After cooling to room temperature, the solution wasfiltered and precipitated in diethylether. The resulting PHP was driedunder reduced pressure at 50° C. This procedure was repeated threetimes. The purified PHP had an intrinsic viscosity of 5.5 dL/g(m-Cresol, 25° C.). The chain extenders 1,4-butanediisocyanate (BDI) and1,12-dodecyldiisocyanate (DDI, Aldrich Chemical Company Inc.) weredistilled under reduced nitrogen pressure prior to use. The BDI.BDO.BDIchain extender was synthesized following the procedure of De Groot, etal. in Polym. Bull. 1998, 41, 299-306. All solvents (Acros Organics orAldrich Chemical Company Inc.) were purified and dried according toliterature procedures.

Network Formation

The networks were synthesized by two different techniques using avariety of polyalcohols and solvents. Polyalcohol was dissolved in NMP,polyvinylalcohol in DMSO and polyvinyl alcohol-co-ethylene in NMP. Insome cases, the polyalcohols (polyalcohol and polyvinylalcohol) werefirst butylated (5% or 10%) at 80° C. for 3 hours by addition ofbutylisocyanate in a small amount of solvent. The polymer was thanprecipitated in dietylether and dried under reduced pressure. Butylatedpolyvinylalcohol turned out to be soluble in NMP and thus crosslinkingwas carried out in that solvent.

Technique 1: The polyalcohol or butylated polyalcohol was dissolved inthe appropriate solvent (5% w/w) and kept at 80° C. In the case ofin-situ butylation, the appropriate amount of n-butylisocyanate in asmall amount of solvent was added followed by 3 hours of reaction. Thepolyalcohol was crosslinked in solution by addition of the chainextender in a small amount of solvent. After homogeneition of thereaction mixture and 3 minutes of reaction, the reaction mixture waspoured onto a petri dish and placed on a heating plate at 7° C. Thesolvent was allowed to evaporate at this temperature under a stream ofnitrogen gas and the dry network film was post-cured at 70° C. for 20hours. The resulting dry network was further dried under reducednitrogen pressure at 50° C.

Technique 2: The polyalcohol was dissolved in the appropriate solventand kept at 80° C. In some cases, the polyalcohol was butylated (5% or10%) at 80° C. by addition of the appropriate amount ofn-butylisocyanate in a small amount of solvent followed by 3 hours ofreaction. Crosslinking was performed at 80° C. by addition of theappropriate amount of chain extender in a small amount of solvent. Afteraddition of the crosslinker, the reaction mixture was homogenized for 3minutes and poured onto a glass-plate with a teflon ring. A second-glassplate was used to close the cell in such way that no gas bubbles wereincluded. The cell with the reaction mixture was placed in an oven at 8°C. for 40 hours. Subsequently, the upper glass-plate was removed and thesolvent was allowed to evaporate at 80° C. The resulting transparentnetworks were stored at 50° C. under reduced pressure.

Compression Molding of Polyallylalcohol

Polyallylalcohol was compression molded at 150° C. for 10 minutes. Amold with a diameter of 2 cm and a thickness of 1.5 mm was used. A forceof 300 kN was applied during a Pasadena Hydrualics Inc. hydraulic press.

Network Characterization

Differential scanning calorimetry (DSC) was carried out with aPerkin-Elmer DSC-7 differential scanning calorimeter using sampleweigths of 5-10 mg with a heating rate of 10° C./min. over thetemperature range of −100 to 250° C.

Tensile testing was performed on rectangular-shaped specimens(40×1.0×0.35 mm), cut from thin films at room temperature using anInstron (4301) tensile tester, equipped with a 100 N load cell and anextension rate of 10 mm/min. For determination of the permanent set, a10 N load cell was used.

Optical transmissions were determined using a SLM Aminco 3000 ArrayMilton Roy spectrophotometer in the of λ=200-800 nm.

After immersing the network films in water at the appropriatetemperature, equilibrium water contents (EWC) were determined using thefollowing formula:EWC(%)=(P _(sw) −P _(d))/P _(sw)

In which P_(sw) refers to the mass of the swollen network and P_(d) tothe mass of the network in the dry state.

Polymer Syntheses

Poly(1-hydroxy-1,3-propanediyl)

Poly(1-hydroxy-1,3-propanediyl) (PHP) was synthesized from polyketone,being a stereoregular perfectly alternating copolymer of ethylene andcarbon monoxide. The reduction was carried out in a 50/50 mixture ofethanol and water using sodium boron hydride as reducing agent, seeLommerts, B. J.; Ph.D. Thesis, University of Groningen, The Netherland,1994. Although polyketone is only slightly soluble in mixtures ofethanol and water, the reduction can be carried out in this solventsystem because the resulting polyalcohol is soluble. Solvation of theresulting polyalcohol is thus the driving-force for the completion ofthe reaction. For high molecular weight samples, long reaction times (24h.) were needed in order to obtain complete conversion. It also turnedout to be crucial to use finely powdered polyketone in order to create alarge surface area. Powdering was performed at liquid nitrogentemperatures. The resulting poly(1-hydroxy-1,3-propanediyl wasextensively purified by subsequent filtration and precipitation. Inorder to assure complete transparency of the polymer solution, thisprocedure was repeated three times.

Polyvinylalcohol

High molecular weight polyvinyl alcohol is not commercially availableand was thus synthesized following the procedure of Sakurada et al. Highmolecular weight polyvinylacetate was hydrolyzed using methanol incombination with aqueous NaOH. The resulting polymer precipitated fromthe solution and was purified by washing with methanol. Also acommercially available EVA co-polymer (of ethylene and vinylalcohol) hasbeen used, having 27% ethylene and 73% vinylalcohol (EVA (27/73)).

Polyallylalcohol

High molecular weight polyallylalcohol was synthesized by reduction ofhigh molecular weight polymethylacrylate with a four-fold excess oflithium aluminum hydride following the procedure of Schulz et al. Thereaction was carried out in THF. The polymer, however, turned out to beinsoluble in organic solvents. Only combinations of organic solvents andaqueous acid could be used, e.g. methanol/2M hydrochloric acid 1/1 orTHF/2M hydrochloric acid 1/1. It is known that in the case of Pn<350 thepolymer is also soluble in organic solvents.

Network formation; Crosslinkers

All the described polymers, plus polyvinylalcohol-co-ethylene have beencrosslinked in solution. A number of different isocyanate crosslinkershave been used. Compared with conventional acrylate crosslinkers, themain difference is that acrylates crosslinking occurs in anuncontrolled, radical reaction whereas isocyanates react in a stepreaction, resulting in more homogeneous networks. As representative fora short crosslinker, 1,4-butanediisocyanate has been used.1,12-Dodecyldiisocyanate and the BDI.BDO.BDI block have been used aslonger crosslinkers. The main difference between the latter two is that1,12-dodecyldiisocyanate is rather apolar whereas the BDI.BDO.BDI blockis more polar and able to form (more) hydrogen bonds (after reaction).1,4-Butanediisocyanate and 1,12-dodecyldiisocyanate are highly reactivewhereas the BDI.BDO.BDI chain extender is far less reactive. Thisproperty is important because it allows homogeneous mixing of thereactants. The two different applied techniques will now be discussed aswell as the properties of the resulting networks.

Technique 1: In this case, the polymer was dissolved at a concentrationof 5% and the crosslinker was added in a small amount of solvent. Afterhomogeneition at 80° C. the network was allowed to form at thattemperature and the solvent was evaporated simultaneously. In the caseof 1,4-butanediisocyanate as chain extender homogeneition was difficultdue to the high reactivity of the diisocyanate. In some cases, a gel wasobtained before proper mixing. After further drying of the networksunder reduced pressure, the properties of the networks were determined.For each entry, a series of networks was made usually varying incrosslink percentage from 0.5 to a maximum of 20%. The different seriesare summarized in Table 1. TABLE 1 Summary of polymer networkssynthesized by technique 1. Entry Polymer Solvent CrosslinkerButylisocyanate (%) Appearance 1 PHP NMP BDI 0 Opaque 2 PHP NMP DDI 0Opaque 3 PHP NMP BDI.BDO.BDI 0 Slightly turbid 4 EVA (27/73) NMP BDI 0Clear 5 EVA (27/73) NMP BDI.BDO.BDI 0 Clear 6 PVA NMP BDI.BDO.BDI 5Clear

Of the resulting polymer networks, the equilibrium water content (EWC)was determined as a function of crosslink percentage and as a functionof temperature. The networks obtained by crosslinking with a shortreactive isocyanate (1,4-butanediisocyanate) or a long reactiveisocyanate (1,12-dodecyldiisocyanate) are opaque. This results from thehigh reactivity of diisocyanate, giving rise to an inhomogeneousreaction mixture. Furthermore, the apolar nature of 1,12-diisocyanatemay give rise to a phase separated morphology. The BDI.BDO.BDIcrosslinker has a lower reactivity than the other diisocyanates and israther polar. The resulting networks were usually slightly turbid. Athigher crosslink percentages (generally >4%), syneresis was observed forEVA and PVA based networks, indicating that in these cases elasticforces play an important role at higher crosslink percentages. ThePoly(1-hydroxy-1,3-propanediyl) based networks generally did not showthis effect. For the poly(alcohol) based network, the equilibrium watercontent as a function of crosslink percentage is shown in FIG. 1. As canbe seen from FIG. 1, the equilibrium water content linearly decreaseswith increasing crosslink density. The decrease, however, is relativelysmall. The equilibrium water content is also affected by thetemperature. The general trend is a decrease in EWC with increasingtemperature. A representative example will be shown for Technique 2. Thecopolymers of ethylene and vinylalcohol all result in transparentnetworks. However, the equilibrium water content is rather low in allcases although the composition in terms of hydrogen, oxygen and carboncontent is comparable to poly(1-hydroxy-1,3-propanediyl) This may becaused by the blockyness of the copolymer or branching, resulting in analtered morphology. The equilibrium water content as function ofcrosslink density for both BDI and the BDI.BDO.BDI crosslinker in nearlyconstant with crosslink density and lies around 17%. The equilibriumwater content for polyvinyl alcohol is known to be rather high. However,addition of a small amount of n-butylisocyanate (5%) and crosslinkingwith the BDI.BDO.BDI crosslinker resulted in an equilibrium watercontent of 40%. So in conclusion it can be said that for a number ofpolymers the equilibrium water content can be influenced (tuned) bymodification of the polymer with monoisocyanates or by changing thecrosslink density.

The mechanical properties of the networks were determined in dry and inswollen state, both as a function of temperature and crosslinkpercentage. Due to the opaque appearance of the BDI and DDI crosslinkedpoly(1-hydroxy-1,3-propanediyl), the main focus has been on theBDI.BDO.BDI based networks. The tensile strength as a function ofcrosslink density for both BDI and BDI.BDO.BDI are shown in FIGS. 2 and3, respectively.

As can be clearly seen, both curves of the swollen networks show amaximum in the tensile strength. For the BDI.BDO.BDI crosslinker also amaximum for the dry network is visible. The first part of the curve canbe explained by the decreasing amount of dangling ends with increasingcrosslink density. It can also be seen that the maximum is approximatelyat the same position for both crosslinkers. The Young's moduli of thewater-swollen networks generally vary between 1.5 and 4.0 MPa.Representative stress-strain curves will be shown for Technique 2.

For the EVA polymer networks, the same trends are observed. However,these networks show the maximum at a lower crosslinks percentage.Furthermore, they show a higher tensile strength in the swollen state.This is due to the lower equilibrium water contents of these hydrogels.

Technique 2

In technique 2, a 5% polymer solution was made and optionallyn-butylisocyanate was added followed by 3 hours of reaction.Subsequently, the crosslinker was added and after homogeneition of thereaction mixture (3 minutes), it was transferred to a glass plate with aTeflon ring on it. A second glass plate and a clamp were used to closethe cell and all air was excluded. After reaction, the upper glass platewas removed and the solvent was evaporated.

By using this technique, the volume during crosslinking is keptconstant. This has several implications for the structure of theresulting network. In addition to the constant volume, crosslinking isperformed in a good solvent (NMP) at a low concentration (4-5%). Theconsequences of these three factors are the following: Due to the goodsolvent and the low concentration, the amount of entanglements in thepolymer solution has been minimized. After crosslinking, this results innetworks in wherein a minimal amount of entanglements are trapped.Furthermore, it can be expected that crosslinking has occurred underhomogeneous conditions.

Because the poly(1-hydroxy-1,3-propanediyl) networks (synthesized bymethod 1) showed the most promising behavior, Technique 2 was alsoapplied to this polymer. Furthermore, in order to keep the equilibriumwater content high and the modulus low, a small amount of crosslinkerwas used. The networks that have been synthesized by this method aresummarized in Table 2. TABLE 2 Networks synthesized by Technique 2.Butylisocyanate Entry Polymer Solvent Crosslinker and amount (%) (%)Appearance 1 PA NMP 0.5% BDI.BDO.BDI 0 Clear 2 PA NMP 0.5% BDI.BDO.BDI 5Clear 3 PA NMP 0.5% BDI.BDO.BDI 10  Clear

These networks were all clear. This probably results from the morehomogeneous reaction conditions. The equilibrium water content as afunction of crosslink generally shows the same behavior as in the caseof technique 1. Also the equilibrium water content as a function oftemperature was determined. A representative example(poly(1-hydroxy-1,3-propanediyl) system 1) is shown in FIG. 4.

As can be seen from FIG. 4, higher temperatures result in morepolymer-polymer interactions and thus a decreased solubility (LCST).However, in this case of a low crosslink density and in the absence ofn-butylisocyanate the system turned out to be rather unstable. A suddenincrease or decrease in the temperature often resulted in opaqueness oreven a complete loss of transparency. Sudden change in environment (e.g.removal of the water surrounding the gel) had the same result.

The most likely explanation for this effect is that the homogeneity ofthe system is disturbed resulting in a phase-separated morphology inwhich concentrated polymer phases are present as well as dilute polymerphase. In order to test this hypothesis, small amounts ofn-butylisocyanate were added before crosslinking in order to avoidphase-separation and eventually crystallization. The resulting network(5% n-butylisocyanate, 0.5% BDI.BDO.BDI crosslinker) was transparentand, as expected, far more stable to changes in temperature andenvironment. Also in this case, the equilibrium water content has beendetermined as a function of temperature (FIG. 5).

As can be seen, the general trend is comparable to network 2. However,due to the less hydrophilic nature of the n-butylurethane moietycompared to the hydroxyl group, the equilibrium water content hasdecreased over the whole temperature range. When more n-butylisocyanateis added, the equilibrium water content becomes relatively stable again.The equilibrium water content as a function of n-butylisocyanate groupsis shown in FIG. 6.

From this, it can be concluded that the equilibrium water content of thegels can be influenced both by the addition of side group and thecrosslink percentage. When higher equilibrium water contents aredesired, n-butylisocyanate can be replaced by a less hydrophobicisocyanate like ethylisocyanate. Phenylisocyanate may be an interestingalternative in order to enhance the refractive index of the system. Thismay, however, lead to yellowing of the gel on exposure to light.

Because the equilibrium water content is rather strongly influenced bythe amount of side groups and less by the percentage of crosslinker(vide infra) it is in principle possible to vary the crosslinkingpercentage without affecting the equilibrium water content (withincertain limits). A further experiment that has been performed isdetermination of the equilibrium water content in buffered phosphatesolution (saline). At 37° C., in case of polyalcohol system 2, a smallincrease from 32% to 36% equilibrium water content was observed which issatisfactory for the application. Functionalization withn-butylisocyanate can furthermore be applied to polymers that show toohigh equilibrium water contents for the application. When e.g.polyvinylalcohol is functionalized with n-butylisocyanate, theequilibrium water content can be adjusted to approximately 40%. This 40%was found in the case where the amount of hydroxyl functionalities inPVA was reduced to level in which they are present for polyalcohol. Thewater-swollen network showed a tensile strength of 5.0 MPa.

In view of transparency and mechanical properties, the thermal behaviorof the network is of great importance. For polyalcohol system 2, DSCtraces are shown in FIG. 7.

Apparently, only small amounts of crosslinker and side groups arerequired to eliminate the crystallinity. The melting point of purepolyalcohol is usually found at approximately 120° C. The Tg is found at25° C. allowing folding of the material at room temperature. Compared touncrosslinked polyalcohol, the Tg has been lowered by 15-20° C. Thedependence of the Tg on the percentage of n-butyl functionalization isshown in FIG. 8.

The poly(1-hydroxy-1,3-propanediyl) networks with 0-5% of side groupslook most promising for the application since their equilibrium watercontent is still high enough. Approximately 5% of side chains arepreferred since this prevents phase separation in the swollen gel. Theoptical transmission of the hydrogel with 5% n-butylisocyanate at λ=480nm was found to be >90%.

The low crosslinking percentage has consequences for the mechanicalproperties of both the dry and the swollen networks. A representativestress-strain curve the 5% butylated and 0.5% crosslinked network inboth dry and swollen state is shown in FIG. 9.

In the dry state, the network has a tensile strength of ˜30 MPa. Forthis specific crosslink density, this is in the same order as comparablenetworks synthesized by technique 1 (FIG. 3). After swelling in water,the (uncorrected) tensile strength has decreased by a factor 2 (15 MPa).The water-swollen network still has a considerable Young's modulus butat strains greater than 50%, the modulus approaches 0. The somewhathigher modulus at the beginning of the curve may be caused by thedisruption of small crystallites. However, DSC measurements did notreveal any crystallinity. The low modulus after 50% strain is caused bythe absence of entanglements, allowing the polymer chains to rearrangefreely on increasing strain. This feature is important in order to applythese types of networks for accommodating lens systems. At the end ofthe curve, an upturn effect is observed, indicating orientedcrystallization. The stress-strain curves of drypoly(1-hydroxy-1,3-propanediyl) networks with different amounts ofn-butylisocyanate groups are shown in FIG. 10. In FIG. 10, two effectscan be observed. In case of 5% side groups, the Tg was observedapproximately at room temperature and the material has a rather highmodulus. When 10% of n-butylisocyanate was added, the Tg decreases to18° C. (FIG. 8) and the modulus decrease dramatically. At the end of thecurve, an upturn effect is observed indicating oriented crystallization.When the amount of side groups is increased to 25% orientedcrystallization is prevented and the upturn effect vanishes. Thestress-strain curve of the corresponding hydrogels is shown in FIG. 11.

In the case of water-swollen networks, the Tg's have decreased to valuesbelow room temperature and all hydrogels exhibit identical stress-strainbehaviors up to 250% strain. However at higher strains the network with5% side groups shows a considerable up-turn effect indicating orientedcrystallization. Also viscoelastic contributions may play an importantrole, since the Tg was found near room temperature. In the case of moreside groups these effects decrease. Considering accommodating lenssystem it is important to study the permanent deformation of thewater-swollen networks. The gel was cyclically deformed two times to100% strain. After three minutes, a third cycle was recorded. The firstand the third cycle are shown in FIG. 12.

As can be seen from FIG. 12, the permanent deformation lies around 5%,which is rather low. A hysteresis loop is observed indicating non-idealrubber behavior. In the third cycle, an increase in modulus is observed.This results from the slow evaporation of water out of the gel. Thepermanent deformation and the hysteresis loop are indications that smallcrystallites are present. The networks, however, are clear indicatingthat the crystallites are smaller than the wavelength of light.

Compression Molding

Since high molecular weight polyallylalcohol is insoluble in organicsolvents, the polymer was processed by compression molding at 150° C.The DSC thermogram showed a Tg at 52° C. and no indication ofcrystallinity, see FIG. 13. The brittle and dry polymer was swollen inwater at 25° C. and the equilibrium water content of the correspondingtransparent soft polymer gel was determined to be 45%. This value is inthe same order as the poly(1-hydroxy-1,3-propanediyl) networks and makesthe material suitable for the application. Although the polymer isinsoluble in water and reptation of polymer chains is expected to beslow crosslinked systems are preferred in view of permanent set ondeformation. An interesting possibility is to swell smallpolyallylalcohol particles in crosslinker solution followed by removalof the solvent and compression molding. Bu such a method a homogenouspolymer/crosslinker mixture can be obtained resulting in homogenouspolymer networks after crosslinking.

1. A hydrogel comprising a network of hydrophilic polymers havinghydroxyl group carrying carbon to carbon backbones having a tensilestrength of at least 1 MPa.
 2. A hydrogel according to claim 1 having anelasticity modulus less than about 10 kPa, preferably less than about 5kPa.
 3. A hydrogel according to claim 1 having a tensile strength of atleast about 5 MPa.
 4. A hydrogel according to claim 1 having anelongation of at least 50% at equilibrium water content.
 5. A hydrogelaccording to claim 1 having sufficient optical clarity so as to obtainan optical transmission of at least about 40%.
 6. A hydrogel accordingto claim 1 having a refractive index of at least about 1.40.
 7. Ahydrogel according to claim 1, wherein the hydrophilic polymers have amolecular weight of at least 200 000, preferably at least 300
 000. 8. Ahydrogel according to claim 1 having a polymer content between about 30to 80% (wt), preferably between about 40 to 70% (wt).
 9. A hydrogelaccording to claim 1, wherein the hydrophilic polymer is chemicallymodified with agent capable of reducing its equilibrium water content.10. A hydrogel according to claim 9, wherein said agent is amonoisocyanate.
 11. A hydrogel according to claim 10, wherein saidmonoisocyanate is a lower alkyl, aryl or arylalkyl isocyanate.
 12. Ahydrogel according to claim 1 wherein the hydrophilic polymer isselected from at least one of the polymers —(CH₂—CHOH)_(n)— (polyvinylalcohol); —(CH₂—CH₂)_(n)(CH₂—CHOH)_(m)— (copolymer of ethylene and vinylalcohol); —(CH₂—CH₂—CHOH)_(n)— (poly(1-hydroxy-1,3-propanediyl) and—(CH₂—CH(CH₂OH))_(n)— (polyallyl alcohol).
 13. A hydrogel according toclaim 12, wherein the hydrophilic polymer is polyallyl alcohol.
 14. Ahydrogel according to claim 1, wherein the network is formed bycrosslinks between the hydrophilic polymers.
 15. A hydrogel according toclaim 14, wherein the crosslinking density is less than about 10%,preferably less than about 5%.
 16. A hydrogel according to claim 15crosslinked by means of a diisocyanate.
 17. A hydrogel according toclaim 16, wherein said diisocyanate has a formulaOCN—(CH₂)₄—NH—C(O)O—(CH₂)₄—O(O)C—NH—(CH₂)₄—NCO.
 18. A hydrogel accordingto claim 16 having crosslinks of the formula —O—C(O)—NH—R—NH—C(O)—O—,wherein R is a spacing group.
 19. A hydrogel according to claim 9,wherein R is an optionally substituted lower alkyl group having betweenone and ten carbon atoms.
 20. A hydrogel according to claim 19, whereinR is —(CH₂)₄—
 21. A hydrogel according to claim 14 crosslinked by meansof an epoxy compound.
 22. A hydrogel according to claim 12, wherein thehydrophilic polymer poly(1-hydroxy-1,3-propanediyl.
 23. A hydrogelaccording to claim 22 crosslinked with diisocyanates.
 24. A hydrogelcomprising poly(1-hydroxy-1,3-propanediyl) crosslinked with a loweralkyl diisocyanate.
 25. A hydrogel according to claim 24, wherein saidlower alkyl diisocyanate is 1,4-butanediisocyanate.
 26. A hydrogelaccording to claim 24, wherein the hydroxyl groups ofpoly(1-hydroxy-1,3-propanediyl is modified with a monoiscyanate beforebeing crosslinked with a lower alkyl diisocyanate.
 27. An implant madeof a hydrogel according to any of claims 1 to 26
 28. An ophthalmic lensmade of a hydrogel according to any of claims 1 to
 24. 29. An ophthalmiclens according to claim 27 having (a) an elasticity modulus less thanabout 10 kPa, preferably less than about 5 kPa; (b) a tensile strengthof at least about 1 MPa; (c) an elongation of at least 50% atequilibrium water content; (d) sufficient optical clarity so as toobtain an optical transmission of at least about 40%; and (e) arefractive index of at least about 1.40.
 30. A method of preparing ahydrogel having a low elasticity modulus from a hydrophilic polymercomprising the steps of: (a) selecting hydrophilic polymer ofsufficiently high molecular weight; (b) dissolving said polymer in agood solvent to a concentration not exceeding about 5% (wt); (c) addinga crosslinking agent; (d) mixing and reacting polymer with crosslinker;(e) evaporating said solvent; (f) optionally adding water.
 31. A methodaccording to claim 30, wherein the crosslinking agent is a diisocyanate.32. A method according to claim 30, wherein the hydrophilic polymer hasa molecular weight of at least about 200 000, preferably at least about300
 000. 33. A method according to claim 30 further comprising degassingthe solution of polymer in good solvent.
 34. A method according to claim30 further comprising the step of chemically modifying the polymer so asto reduce its hydrophilicity.
 35. A method according to claim 30,wherein the hydrophilic polymers have hydroxyl group carryingcarbon-carbon backbone
 36. A method according to claim 35, wherein thehydrophilic polymers are selected from at least one of the polymers—(CH₂—CHOH)_(n)— (polyvinyl alcohol); —(CH₂—CH₂)_(n)(CH₂—CHOH)_(m)—(copolymer of ethylene and vinyl alcohol); —(CH₂—CH₂—CHOH)_(n)—(poly(1-hydroxy-1,3-propanediyl)) and —(CH₂—CH(CH₂OH))_(n)— (polyallylalcohol).
 37. A method according to claim 35 characterized by modifyingthe hydrophilic polymer by reacting it with a mono-isocyanate.
 38. Amethod according to claim 37 characterized by modifying less than 15%,preferably less than 10% of their hydroxyl groups.
 39. A methodaccording to claim 30 characterized by performing the crosslinking atconstant volume.
 40. A method according to claim 30 resulting in theformation of a hydrogel having an elasticity modulus less than about 10kPa, preferably less than about 5 kPa.
 41. A method according to claim36 wherein the hydrophilic polymer is (poly(1-hydroxy-1,3-propanediyl).42. A method according to claim 41 wherein the crosslinker is adiisocyanate.